Abstract
Background/Aim: Impact of second-line chemotherapy in unresectable advanced/recurrent gastric/esophagogastric junction cancer (AGC) remains unclear. This retrospective analysis aimed to identify factors affecting prognosis in chemotherapy for patients with AGC, including the importance of progression-free survival in second-line chemotherapy (PFS-2). Patients and Methods: Data from a total of 109 patients with AGC that received second-line treatment were analyzed with the aim of clarifying prognostic factors. Furthermore, the correlation between PFS-2 and clinical characteristics and the association between PFS-2 and inflammation-based and/or nutritional markers were investigated. Results: Multivariate analysis identified the following prognostic factors: ECOG PS ≥1, presence of peritoneal dissemination, metastasis in two or more organs, and taxane use on second-line chemotherapy. Short PFS-2 was strongly associated with prognosis in the univariate analysis [hazard ratio (HR)=3.107, 95% confidence interval (CI)=1.969-4.904, p<0.001]. The duration of PFS-2 was significantly correlated with ECOG PS (p=0.019), liver metastasis rates (p=0.035) and taxane use on second-line chemotherapy (p=0.001). In addition, weight loss rate during first-line treatment (p=0.042), white blood cell count (p=0.008), C-reactive protein (p=0.032), c-reactive protein to albumin ratio (p=0.039), prognostic index (p=0.028), and modified Glasgow prognostic score (p=0.027) were significantly associated with the duration of PFS-2. Conclusion: The duration of PFS-2 significantly correlated with ECOG PS, liver metastasis, and taxane use on second-line treatment, and strongly affected OS. It was suggested that the presence of malnutrition and inflammation at the start of second-line therapy had a negative impact on PFS-2 and OS.
- Progression-free survival in second-line chemotherapy
- advanced gastric cancer
- malnutrition
- inflammation
The Japanese Gastric Cancer Treatment Guidelines (1) recommend systemic chemotherapy for prolonging survival and alleviating symptoms in patients with unresectable advanced/recurrent gastric cancer (AGC). Overall survival (OS) and progression-free survival (PFS) rates in patients with AGC have been estimated in the range of 10.5-14.1 months and 2.9-6.0 months, respectively (2-6). In Japan, combination therapy with oral fluoropyrimidine and platinum is recommended as standard first-line treatment for human epidermal growth factor 2 (HER2)-negative AGC (1). In contrast, patients with HER2-positive AGC are recommended the addition of trastuzumab as the first-line treatment based on the results of the ToGA trial (7). A combination of oxaliplatin-based chemotherapy and nivolumab, an immune checkpoint inhibitor, has been reported to improve OS and PFS rates when used as first-line treatment for AGC (8). However, the ATTRACTION-4 study reported no improvements in OS estimates associated with this therapy in Asian populations (9). As a second-line treatment for AGC, the combination of ramucirumab with paclitaxel improved OS outcomes (10); it is recommended by the Japanese Gastric Cancer Treatment Guidelines regardless of HER2 status (1). As third-line treatment for AGC, trastuzumab deruxtecan (11) is recommended for HER2-positive AGC, and nivolumab (12) and trifluridine/tipiracil (13) are recommended for HER2-negative AGC. The DESTINY-Gastric 01 phase 2 trial (11) reported an objective response rate of 51% among patients treated with trastuzumab deruxtecan, as compared with the rate of 14% among patients treated with physician’s choice therapy (p<0.001). OS rates associated with trastuzumab deruxtecan were better than those associated with chemotherapy [median, 12.5 vs. 8.4 months; hazard ratio (HR) for death, 0.59; 95% confidence interval (CI)=0.39-0.88; p=0.01].
AGC outcomes are associated with the choice and timing of regimen. Multivariate analysis using the JCOG9912 trial data revealed that factors such as PS of ≥1, number of metastatic organs ≥2, no prior gastrectomy, and elevated alkaline phosphatase levels may affect chemotherapy outcomes in AGC (14). First-line treatment may be key to achieving good outcomes; nevertheless, second-line treatment may also help improve OS. A meta-analysis investigating the association between post-progression survival and OS after first-line treatment for patients with AGC revealed a significant correlation between these outcomes, which was further validated in a 2006 trial (15). Other studies have suggested that, alongside tumor-related factors, inflammation-based and/or nutritional markers, such as c-reactive protein to albumin ratio (CAR) (16, 17), prognostic index (PI) (18, 19), neutrophil to lymphocyte ratio (20, 21), Glasgow prognostic score (GPS) (22), and modified Glasgow prognostic score (mGPS) (23) may contribute to ACG outcomes.
This study aimed to identify prognostic factors including clinicopathological characteristics and inflammation-based and/or nutritional markers associated with systemic chemotherapy for patients with AGC. This study also aimed to examine the importance of progression-free survival (PFS) in second-line chemotherapy (PFS-2) and its correlation to OS. These findings may help improve outcomes in patients with AGC.
Patients and Methods
Patients and data collection. This single-center retrospective study included patients with unresectable advanced or recurrent gastric cancer and esophagogastric junction cancer that was histologically confirmed to be adenocarcinoma and who were treated with one previous chemotherapy cycle from January 2012 to July 2021 at Gunma University Hospital. Among 156 patients with metastatic or recurrent gastric cancer and esophagogastric junction cancer who received first-line treatment, 1 patient with complete remission, 3 patients with under first-line treatment, and 43 patients who received best supportive care after first-line treatment were excluded. Finally, this study included 109 patients (Figure 1). Data on patient demographic and clinical characteristics were extracted from medical records, including sex, age, Eastern Cooperative Oncology Group Performance Status (ECOG PS), disease status (metastatic or recurrence), primary site (gastric or esophagogastric junction), histological type (Lauren classification), HER2 status, site of metastasis, organs with metastasis, and treatment regimens.
Study profile. Patients with advanced/recurrent gastric/esophagogastric junction cancer (AGC) (n=109) given second-line treatment were enrolled in this study (156 patients with AGC received first-line treatment). The true transition rate to the subsequent therapy was calculated from the number of patients who should be treated with the subsequent line (excluding patients in remission or continuing previous-line treatment) and that of patients who could be transitioned to the subsequent therapy.
Outcomes and survival assessment. The median OS and PFS were calculated by the Kaplan-Meier method. OS was assessed from the date of first-line treatment initiation until death from any cause or was censored at the latest follow-up for surviving patients. PFS was defined as the period between the date of each treatment initiation to the date of disease progression or disease-related death.
Assessment of nutritional status and inflammation-based serum biomarkers. Body weight change was calculated at the start of second-line treatment, relative to baseline values obtained at the start of first-line treatment. The following laboratory test results were considered: white blood cell count (WBC), albumin (ALB) and C-reactive protein (CRP) values. The CAR was calculated as CRP/ALB. The mGPS was calculated using CRP levels of 0.5 mg/dl and ALB levels of 3.5 g/dl as standard values (23). Patients with elevated CRP levels (>0.5 mg/dl) and hypoalbuminemia (<3.5 g/dl) were allocated a score of 2 points. Patients with only one factor were allocated a score of 1 point, and those with neither factor were allocated a score of 0 points. The PI was determined based on WBC of 11,000 cell/mm3 and CRP level of 1.0 mg/dl as the standard values (19). Patients with elevated CRP levels (>1.0 mg/dl) and elevated WBC (>11,000/μl) were allocated a score of 2 points. Patients with only one factor were allocated a score of 1 point, and those with neither factor were allocated a score of 0 points.
Statistical analysis. Differences between the groups were compared using Fisher’s exact test for categorical variables and the Mann-Whitney U-test for continuous variables. OS and PFS estimates were obtained with the Kaplan-Meier method and compared using the log-rank test. The Cox proportional hazards regression model was used to calculate HRs with 95%CIs. Factors associated with OS were identified with univariate analyses; factors identified as statistically significant in univariate analyses (p-values <0.1) were included in multivariate models. All data were analyzed using EZR, which is a freely available easy-to-use medical statistical software package and available on website (24). p-Values of <0.05 were considered statistically significant.
Ethics approval and consent to participate. The study was carried out in accordance with the Helsinki Declaration. The study protocol was approved by the institutional review board of Gunma University Hospital, approval number HS2022-022. The regimen details, possible adverse events and expected effects of systemic chemotherapy for gastric or esophagogastric junction cancer was explained and informed consent obtained from all the patients. On the other hand, the requirement for acquisition of informed consent from patients for this study was waived by the institutional review board of Gunma University Hospital because of the retrospective design of this study and anonymised data.
Results
Clinical characteristics of patients. Data from 109 patients were analyzed in this study (1). The true transition rates to second-line, third-line, fourth-line, and fifth- or later-line treatments were 72%, 41%, 19%, and 11%, respectively. The patients’ baseline characteristics are summarized in Table I. Overall, 74% of the patients were male and the median age at the time of first-line treatment initiation was 66 years (range=31-85 years). A total of 64 (59%), 40 (37%), 5 (4%), 62 (57%), 47 (43%), 88 (81%), and 21 (19%) patients were diagnosed with ECOG PS0, 1, 2, unresectable metastatic cancer, recurrent cancer following curative resection, gastric cancer, and esophagogastric junction cancer, respectively. In addition, 42 (39%) patients had intestinal type adenocarcinoma and 13 (12%) patients had HER2-positive disease. Furthermore, 58 (53%) and 51 (47%) patients had metastasis to one and two or more organs, respectively. In first-line treatment, 108 (99%), 96 (88%), and 11 (10%) patients received regimens containing pyrimidine analogs, platinum, and trastuzumab, respectively. In second-line treatment, 99 (91%) and 67 (61%) patients received regimens containing taxane and ramucirumab, respectively. The median OS estimates for first-line and second-line treatment were 18.37 months (95%CI=17.22-22.51 months) and 10.87 months (95%CI=17.22-22.51 months), respectively. The median PFS of first-line and second-line were 5.85 and 4.34 months, respectively.
Characteristics of patients given second-line treatment for unresectable metastatic or recurrent gastric and esophagogastric junction adenocarcinoma.
Prognostic factors for overall survival. The results of univariate and multivariate Cox proportional hazards regression are shown in Table II. Female sex, poor ECOG PS (≥1), peritoneal dissemination, and short PFS-2 were associated with poor outcomes in univariate analysis. In multivariate analysis, ECOG PS ≥1 (HR=1.060, 95%CI=1.014-1.109, p=0.001), presence of peritoneal dissemination (HR=2.136, 95%CI=1.162-3.928, p=0.015), metastasis in two or more organs (HR=2.199, 95%CI=1.360-3.557, p=0.001), and taxane use on second-line chemotherapy (HR=0.411, 95%CI=0.190-0.891, p=0.024) were identified as an independent prognostic factors in patients with AGC. The Kaplan-Meier method revealed that OS was significantly longer in patients that had long PFS-2 compared with PFS in first-line (Figure 2).
Results of univariate and multivariate Cox proportional hazards regression for overall survival (n=109).
Kaplan-Meier analysis of overall survival according to the progression-free survival (PFS) in first-line (A) and second-line (B).
Association between clinical characteristics and duration of PFS-2. Patient clinical characteristics associated with PFS-2, which strongly correlates with OS, are presented in Table III. The duration of PFS-2 was significantly correlated with ECOG PS (p=0.019), liver metastasis rates (p=0.035) and taxane use on second-line treatment (p=0.001). Eight (14%) patients that used neither taxane nor ramucirumab as second-line treatment had below median PFS-2.
Characteristics of patients by duration of progression-free survival in second-line chemotherapy (PFS-2) (n=109).
Relationship between CAR, PI, mGPS and duration of PFS-2. The associations between systemic inflammation and nutritional status at the start of second-line treatment and PFS-2 are presented in Table IV. Weight loss rate (p=0.042), WBC (p=0.008), CRP level (p=0.032), CAR (p=0.039), PI (p=0.028), and mGPS score (p=0.027) were significantly associated with the duration of PFS-2.
Correlation between progression-free survival in second-line chemotherapy (PFS-2) and systemic nutrition and inflammatory status at the start of second-line treatment (n=109).
Discussion
This retrospective study revealed that short PFS-2 was a strong predictor of poor outcomes in patients with AGC. In addition, the shortness of PFS-2 was associated with liver metastasis and non-use of taxane in second-line treatment. Furthermore, systemic nutrition and inflammatory status at the start of second-line treatment were associated with PFS-2. This evidence indicates that second-line treatment will strongly impact OS outcomes in patients with unresectable metastases or recurrent gastric and esophagogastric junction cancer.
Pyrimidine fluoride and platinum combination therapy is recommended as first-line treatment for AGC; the addition of trastuzumab or nivolumab significantly improved the prognosis in HER2-positive (7) and HER2-negative (8, 9) AGC, respectively. Despite improvements in OS, the prognosis of patients with AGC remains poor. Second-line chemotherapy may affect outcomes in several types of cancer (25, 26). Herein, PFS-2 was more strongly associated with OS rates than PFS in first-line chemotherapy among AGC patients who transitioned to second-line therapy. Following the results of the RAINBOW trial (10), the ramucirumab and paclitaxel combination therapy is recommended as a second-line treatment for AGC, showing improved outcomes. In the subgroup analysis of the RAINBOW trial, no predictive biomarkers for ramucirumab efficacy in gastric cancer were identified (27). Fuchs et al. (28) reported the following 12 independent prognostic factors in second-line treatment using ramucirumab for AGC: 1) peritoneal metastases; 2) Eastern Cooperative Oncology Group performance score of 1 point; 3) primary tumor presence; 4) time to progression since prior therapy of less than 6 months; 5) poor/unknown tumor differentiation; abnormally low blood levels of 6) albumin, 7) sodium, and/or 8) lymphocytes; and abnormally high blood levels of 9) neutrophils, 10) aspartate aminotransferase, 11) alkaline phosphatase, and/or 12) lactate dehydrogenase. In addition, Mansoor et al. (29) reported that weight loss of ≥3% during the first cycle of chemotherapy was a negative prognostic factor for OS in patients with advanced gastric and esophagogastric junction adenocarcinoma.
In addition, the effectiveness of trifluridine/tipiracil and ramucirumab (30) and ramucirumab plus irinotecan combination therapy (31) as second- or later-line chemotherapy for AGC has been reported. Kawazoe et al. (30) reported that trifluridine/tipiracil and ramucirumab showed an acceptable safety profile and clinical activity in patients with previously treated advanced gastric cancer regardless of previous ramucirumab exposure. In the HGCSG1603 trial (31), PFS and OS estimates in patients receiving combination therapy of ramucirumab plus irinotecan were 4.2 months and 9.6 months, respectively, indicating suitable safety and efficacy profiles. Ramucirumab plus trifluridine/tipiracil or ramucirumab plus irinotecan may be considered to use in these cases where taxanes are not suitable as second-line chemotherapy (i.e., patients with severe peripheral neuropathy at the start of second-line treatment after use of oxaliplatin or patients who cannot accept hair loss). However, it is important to note that these regimens are not currently considered standardized treatments. Furthermore, conversion surgery can be performed depending on the therapeutic effect of second-line chemotherapy, leading to further improvement of OS (32-34). These cases further support the importance of second- or later-line chemotherapy.
Previous studies have reported associations between systemic inflammatory markers and/or nutritional status and carcinoma prognosis (16-23). Second- and later-line therapy may be more important to AGC outcomes than first-line therapy (35). Cancer cachexia may increase the risk of adverse events and reduce the effectiveness and continuity of treatment in multimodal cancer therapy (36). Therefore, maintaining or improving nutritional status during treatment and reducing the extent of systemic inflammatory response may improve prognosis. CRP, which is an element of mGPS and CAR, is a type of acute phase protein produced by the liver in response of IL-6. Chronic increases in CRP levels in cancer patients may indicate the degree of inflammation in cancer tissue, with CRP and albumin levels increasing and decreasing in the acute phase, respectively. In this study, patients with low CAR, PI, and mGPS values at the start of second-line treatment had a mild systemic inflammatory response and good nutritional status, leading to improvement in PFS-2. Previous studies reported that in patients with colorectal cancer who received chemotherapy, fish oil supplements containing eicosapentaenoic acid and docosahexaenoic acid helped reduce CAR and prevent weight loss (37, 38). In patients with cancer-related cachexia associated with weight and muscle mass loss, anorexia, systemic inflammation, and insulin resistance, treatment with anamorelin, which is an oral ghrelin-receptor agonist with appetite-enhancing and anabolic activity, may help counteract some of these effects (38). Anamorelin treatment for 12 weeks had a favorable clinical response profile characterized by a significant increase in lean body mass in patients with cancer anorexia-cachexia syndrome [difference 2.09 kg (0.94-3.25); p=0.0006] (39). Herein, weight loss from the start of first-line to second-line treatment resulted in shorter PFS-2, which was associated with poor OS. Nutritional supplementation with eicosapentaenoic acid and docosahexaenoic acid and treatment with anamorelin may help prevent weight loss and indirectly improve OS.
This study had some limitations. First, this was a retrospective, single-center, observational study with a small sample size; the presented findings may be affected by selection bias. Second, although based on gastric cancer treatment guidelines, several chemotherapy regimens were determined by clinical preference of each investigator. We could not fully evaluate these regimens. In addition, nivolumab, an immune checkpoint inhibitor, was approved in Japan in 2017, resulting in better OS for patients with AGC. As this study included patients with AGC who received chemotherapy between 2012 and 2021, it is a major limitation that the pre- and post-approval periods for nivolumab were considered together. Future studies are required to validate the present findings.
Conclusion
This retrospective study revealed the impact of subsequent-line chemotherapy after first-line on OS. Presence of peritoneal dissemination, metastasis in two or more organs, and taxane use on second-line chemotherapy were identified as an independent prognostic factors in patients with AGC. PFS-2 was significantly correlated with liver metastasis rates and taxane use on second-line treatment. It was suggested that the presence of malnutrition and inflammation at the start of second-line therapy had a negative impact on PFS-2 and OS. Early nutritional and pharmacological interventions for cancer cachexia may help improve OS outcomes in patients undergoing systemic chemotherapy for AGC.
Acknowledgements
The Authors would like to thank Editage (www.editage.com) for English language editing.
Footnotes
Authors’ Contributions
AS, MSo, KS, and HS were involved in the conceptualization. AS, MSo, KS, and HS edited the manuscript. AS, NH, KT, TW, SU, NN, KO, TO, TS, MSa and HO collected the patients’ data. AS, MSo, and HS analyzed the patients’ data. All of the Authors have read and approved the manuscript.
Funding
This research study has not received any funding from the public or private sector or from any non-profit entity.
Conflicts of Interest
The Authors declare that they have no competing interests in relation to this study.
- Received August 14, 2023.
- Revision received September 23, 2023.
- Accepted September 25, 2023.
- Copyright © 2023 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
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